Effervescent granules and methods for their preparation

ABSTRACT

Disclosed here are effervescent granules having a controllable rate of effervescence. In some embodiments, the such granules comprise an acidic agent, an alkaline agent, a pharmacologically active agent, hot-melt extrudable binder capable of forming a eutectic mixture with the acidic agent and, optionally, a plasticizer. The effervescent granules are made by a hot-melt extrusion process. The present invention also provides a thermal heat process for preparing a pharmacologically active agent containing effervescent granule. In certain aspects, the granules contain pharmacologically active agents such as narcotics, antidiarrheal agents, antiviral agents, anxiolytic agents, a cholesterol lowering agent, an alpha adrenergic blocking agent, a phenanthrene derivative. By way of example, some of the narcotics that may be included in the granules and in the process of preparing the granules include, by way of example: phenanthrene derivatives (e.g., morphine sulfate), and morphine derivatives (e.g., hydromorphone hydrochloride).

The present application claims priority to provisional application No.60/026,991, filed Sep. 20, 1996 and is a continuation-in-part of U.S.application U.S. Ser. No. 08/934,109 filed Sep. 19, 1997, now issued asU.S. Pat. No. 6,071,539.

FIELD OF THE INVENTION

This invention relates to an effervescent composition and a method ofpreparing same. More specifically, it relates to an effervescent granulehaving a controllable rate of effervescence, the granule being made by ahot-melt extrusion process.

BACKGROUND OF THE INVENTION AND DESCRIPTION OF THE PRIOR ART

Effervescent granules have found a variety of uses over the years. Theseinclude dental compositions containing enzymes, contact lens cleaners,washing powder compositions, beverage sweetening tablets, chewabledentifrices, denture cleaners, surgical instrument sterilizers,effervescent candies, as well as many pharmaceutical formulations suchas for analgesics, antibiotics, ergotamines, digoxin, methadone andL-dopa.

Film-coated effervescent granules are known in the art. Polymers such ascellulose acetate phthalate or hydroxypropyl methylcellulose have beenused. Such coatings have been introduced in order to increase tabletstability as well as to control dissolution rate and to targetparticular regions of the gastrointestinal tract.

Hot-melt extrusion as a method of preparing pharmaceutical formulationshas previously been disclosed; however, effervescent formulationsprepared by hot-melt extrusion are not known.

Hot-melt extrusion processes in the art have generally requiredextremely elevated temperatures (>150° C.), which temperatures coulddegrade extruded materials. It has not been appreciated thateffervescent compositions, which are inherently heat labile, can behot-melt extruded without significant degradation or decompaction.

Lindberg (Acta). Pharm. Suec. (1988), 25, 239-246) teaches a continuouswet granulation method for preparing effervescent granules. The processincludes the steps: (1) mixing powdered citric acid and NaHCO₃ in thehopper of a Baker Perkins cooker extruder and granulating the mixturewith ethanol.

U.S. Pat. No. 4,153,678 and British Patent Application Laid-Open No.2083997 disclose effervescent tablets for addition to animal drinkingwater, respectively containing levamisole and vitamins or minerals asactive components. U.S. Pat. No. 3,667,929 discloses that, aneffervescent powdery composition coated by pulverizing active componentssuch as piperazine acid salt, copper sulfate or sodium nitrate, an acidsubstance and carbonate together with a hydrophobic or a slowlydissolving material, is useful as an agent for addition to animaldrinking water or a material for horticultural use.

Effervescence can be defined as the evolution of bubbles of gas in aliquid. As set forth in chapter 6 of Pharmaceutical Dosage Forms:Tablets Volume I, Second Edition. A. Lieberman. ed. 1989, Marcel Dekker,Inc. (the entirety of which is hereby incorporated by reference),effervescent mixtures have been known and used medicinally for manyyears. As discussed in this text, and as commonly employed, aneffervescent tablet is dissolved in water to provide a carbonated orsparkling liquid drink. In such a drink the effervescence helps to maskthe taste of medicaments. However, the use of effervescent tablets toprepare a beverage including medicaments, is not convenient. It requirespreparatory steps before administration of the drug and also requiresthe presence of a suitable mixing container.

Effervescent tablets have also been used in the dental area. Westlake,U.S. Pat. No. 1,262,888, Howell, U.S. Pat. No. 3,962,417 and Aberg U.S.Pat. No. 4,753,792 disclose effervescent dentifrice tablets adapted tofoam in the mouth of a patient so as to provide a tooth cleansingaction.

An effervescent dosage form which incorporates microparticles which aresusceptible to rupture upon chewing or which are adapted to providesubstantially immediate release of the pharmaceutical ingredientscontained in the microparticles is disclosed in U.S. Pat. No. 5,178,878to Wehling et al. The microparticles comprise a drug encapsulated in aprotective material. The microparticles are then mixed with aneffervescent agent and then the mixture compressed into tablets.

Kond et al., in U.S. Pat. No. 5,223,246, disclose a water solubleeffervescent composition prepared by hot-melting (1) an active componentand (2) an acid and a carbonate for effervescent, with (3) a watersoluble adjuvant whose melting point is not lower than 40° C., foraddition to drinking water. The effervescent composition was prepared bymixing the active agent, the acid, the carbonate and the water solubleadjuvant and then heating the entire mixture to melt the adjuvant andsubsequently cooling the mixture to room temperature while stirring toform effervescent particles.

Thus, there is no teaching or suggestion in the art of preparingeffervescent granules by hot-melt extrusion. Despite prior effortstowards developments of suitable effervescent granules, there have beenunmet needs heretofore for improved effervescent granules havingcontrollable rates of effervescence and for methods for theirpreparation.

SUMMARY OF THE INVENTION

The present invention provides an effervescent granule having acontrollable rate of effervescence prepared by hot-melt extruding (i) anacidic agent, (ii) an alkaline-agent, and (iii) a hot-melt extrudablebinder which melting or softening point temperature is less than about150° C. and which is capable of forming a eutectic mixture with theacidic agent. The acidic and alkaline agents should be able toeffervesce when placed in an aqueous solution. A formulation accordingto this aspect of the invention can provide a rate of release of anactive ingredient that ranges from immediate to a delayed or controlledrelease over a prolonged period of many hours.

One aspect of the present invention provides a solid pharmaceuticaldosage form adapted for direct oral administration, i.e., for directinsertion into the mouth of a patient. A dosage form according to thisaspect of the present invention includes a mixture incorporating a waterand/or saliva activated effervescent granule having a controllable rateof effervescence and a therapeutic compound.

According to another aspect of the present invention, it has been foundthat combination of the effervescent granules with the other ingredientscan provide effective taste masking of particularly poor tastingcompounds. This aspect of the invention thus provides a dosage formwhich offers both immediate or extended release and effective tastemasking.

The effervescent granules taught herein can be used in pharmaceutical,veterinary, horticultural, household, food, culinary, pesticidal,agricultural, cosmetic, herbicidal, industrial, cleansing, confectioneryand flavoring applications.

Formulations incorporating the effervescent granules according to oneaspect of the present invention can further include one or moreadditional adjuvants and/or active ingredients which can be chosen fromthose known in the art including flavors, diluents, colors, binders,filler, surfactant, disintegrant, stabilizer, compaction vehicles, andnon-effervescent disintegrants. The effervescent granules themselves do,not generally include therapeutic compounds or other active ingredients.

The present invention also provides a method of preparing aneffervescent granule having a controllable rate of effervescence wherethe method comprises mixing and hot melt extruding a hot-melt extrudablebinder and an acidic agent to form a eutectic mixture which eutecticmixture is then mixed and hot-melt extruded with an alkaline agent toform the effervescent granule. The hot-melt extrusion process hereinadvantageously allows for extremely short exposure times of compounds toelevated temperatures as well as a higher throughput than batchwisehot-melt methods.

In particular embodiments, effervescent granules including apharmacologically active agent are provided. In some aspects, by way ofexample, and while not intending to constitute an exclusive list, thesepharmacologically active agents may comprise, in at least someembodiments, the following pharmacologically active agents: phenanthrenederivatives (e.g. morphine sulfate), synthetic and non-syntheticantidiarrheal agents (e.g. loperamide hydrochloride). In otherembodiments, the pharmacologically active agent may comprise anantiviral agent (e.g. acyclovir), anxiolytic agents (e.g. buspirone),diuretic agents (e.g. hydrochlorthiazide), and morphine derivatives(e.g. hydromorphone hydrochloride). In yet other embodiments, thepharmacologically active agent may comprise antidepressants (e.g.fluoxetine hydrochloride), serotonin agonists (e.g. sumatriptansuccinate), levorotatory isomers of thyroxine (e.g. levothyroxinesodium), cholesterol lowering agents (e.g. simvastatin) and alphaadrenergic blocking agents (e.g. ergotamine tartrate). Moreover, it isanticipated that other therapeutic, pharmacologically active and/oranalgesic compounds may be used in conjunction with the presentformulations of effervescent granules, as well as combinations of thevarious types and classes of pharmacologically active agents describedhere.

Additionally, the present invention provides a thermal heat process forpreparing an effervescent granule formulation comprising apharmacologically active agent. In some embodiments, the methodcomprises combining an acidic agent, a pharmacologically active agent, ahot-melt extrudable binder which can combine with said acidic agent, apharmacologically active agent, and a plasticizer. The inclusion of aplasticizer in the formulation is optional. The acidic agent, alkalineagent, hot-melt extrudable binder and the optional plasticizer may thenbe dry blended to form a mixture. The mixture may then be hot-meltextruded to form a eutectic mixture. The effervescent mixture is thenhot-melt extruded to form effervescent granules having a controllablerate of effervescence. The mixture is then screened and blended afterwhich said mixture is subjected to compression until tablet form isachieved.

In particular embodiments, a thermal heat process for preparingeffervescent granules including a pharmacologically active agent areprovided. In some aspects, by way of example, and while not intending toconstitute an exclusive list, the pharmacologically active agents thatmay comprise at least some embodiments of the effervescent granulesprepared by the present thermal process include: phenanthrenederivatives (e.g. morphine sulfate), synthetic and non-syntheticantidiarrheal agents (e.g. loperamide hydrochloride). In otherembodiments, the pharmacologically active agents may comprise antiviralagents (e.g. acyclovir), anxiolytic agents (e.g. buspirone), diureticagents (e.g. hydrochlorthiazide), and morphine derivatives (e.g.hydromorphone hydrochloride). In yet other embodiments,pharmacologically active agents may comprise antidepressants (e.g.fluoxetine hydrochloride), serotonin agonists (e.g. sumatriptansuccinate), levorotatory isomers of thyroxine (e.g. levothyroxinesodium), cholesterol lowering agents (e.g. simvastatin) and alphaadrenergic blocking agents (e.g. ergotamine tartrate). Moreover, it isanticipated that other therapeutic, pharmacologically active and/oranalgesic compounds may be used in conjunction with the presentformulations of effervescent granules or combinations thereof.

Other features, advantages and embodiments of the invention will beapparent to those skilled in the art from the following description,examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “effervescent granules” means granules thatconsist of an effervescent couple and a suitable hot-melt extrudablebinder and that are prepared by hot-melt extrusion. By “effervescentcouple” is meant a combination of an acidic agent and an alkaline agentthat when combined in the presence of water cause the formation of a gassuch as carbon dioxide, oxygen or chlorine dioxide.

The effervescent granules of this invention can be in the state ofpowder or fine particles to increase the dissolution rate, andpreferably a particle size such that 90% or more passes a 16 mesh (1,000μ) screen, and more preferably a particle size such that more than 90%passes a 18 mesh (850 mu m) screen. Generally, the larger theeffervescent granule, the longer it will take to completelydisintegrate. This is particularly true when there are low levels ofeffervescent couple present in the granules.

Effervescent Granule Components

As used herein, “effervescence” means the evolution of bubbles of gasfrom a liquid as the result of a bubble or gas generating chemicalreaction. The bubble or gas generating reaction of the effervescentcouple in the effervescent granule is most often the result of thereaction of an acidic agent and an alkaline agent. The reaction of thesetwo general classes of compounds produces a gas upon contact with water.

As used herein, the term “acidic agent” refers to any compound ormaterial that can serve as a proton source and can react with thealkaline agent of the invention to form a gas causing a solutioncontaining them to effervesce. The acidic agent can have more than oneacid dissociation constant, i.e. more than one acid functional group.The acidic agent can be any organic or inorganic acid in the free acid,acid anhydride and acid salt form. An acidic agent which is in solidstate at room temperatures and shows pH 4.5 or lower when saturated intowater at room temperatures or its acid alkali metal salts (e.g. sodiumsalt, potassium salt, etc.) can be employed. As the acidic agent for theeffervescent granule, a compound which is not harmful to animalsincluding man is desirably employed. The acidic agent can be tartaricacid, citric acid, maleic acid, fumaric acid, malic acid, adipic acid,succinic acid, lactic acid, glycolic acid, alpha hydroxy acids, ascorbicacid, amino acids and their alkali hydrogen acid salts. And, even in thecase of an acid substance such as phosphoric acid or pyrophosphoric acidor other inorganic acids which is liquid or in liquid state at roomtemperature, when their acid alkali metal salts are solid at roomtemperature, those acid alkali metal salts can be employed as acidicagents. Among the above-mentioned acidic agents, those having arelatively large acid dissociation constant (10³ or more) and a smallhygroscopicity (critical humidity at 30° C. is 40% RH or more) arepreferably employed.

It is preferred if the acidic agent can form a eutectic mixture with abinder. Because these acids are directly ingested, their overallsolubility in water is less important than it would be if theeffervescent granules of the present invention were intended to bedissolved in a glass of water.

As used herein, the term “alkaline agent” means an alkaline compoundthat releases a gas, or causes a solution to effervesce, when exposed toa proton source such as an acidic agent or water. The alkaline agent canbe a carbon dioxide gas precursor, an oxygen gas precursor or a chlorinedioxide gas precursor.

When the alkaline agent is a carbon dioxide precursor, compounds such ascarbonate, sesquicarbonate and hydrogencarbonate salts (in thisspecification, carbonate and hydrogencarbonate, or bicarbonate, aregenerically referred to as carbonate) of potassium, lithium, sodium,calcium, ammonium, or L-lysine carbonate, arginine carbonate, sodiumglycine carbonate, sodium amino acid carbonate can be used. When thealkaline agent is an oxygen gas precursor, compounds such as anhydroussodium perborate, effervescent perborate, sodium perborate monohydrate,sodium percarbonate and sodium dichloroisocyannurate can be used. Whenthe alkaline agent is a chlorine dioxide (ClO₂) precursor, compoundssuch as sodium hypochlorite and calcium hypochlorite can be used. ClO₂can be used as a chemical sterilizer in cleansing operations.

Where the effervescent agent includes two mutually reactive components,such as an acidic agent and an alkaline agent, it is preferred, althoughnot necessary, that both components react completely. Therefore, a ratioof components which provides for equal amounts of reaction equivalentsis preferred. For example, if the acid used is diprotic, then eithertwice the amount of a mono-reactive carbonate alkaline agent, or anequal amount of a all-reactive alkaline agent should be used forcomplete neutralization to be realized. However, in other embodiments ofthe present invention, the amount of either the acidic agent or thealkaline agent can exceed the amount of the other component. This can beuseful to enhance taste and/or performance of a tablet containing anoverage of either component.

By controlling the relative ratio of acidic agent: alkaline agent, theeffervescent granules can be used to regulate the pH of theirenvironment. Thus, the present granules can be used to regulate the pHof body cavities such as the mouth, rectum or vagina.

The ratio of the above-mentioned acidic agent and alkaline agent canalso be determined according to the pH required for dissolving an activeingredient included in a formulation containing effervescent granules orupon other conditions which a user can contemplate. When the solubilityof the active ingredient increases at the acid side, the pH of thesolution is lowered by adding the acidic agent in an amount more thanequivalent to the alkaline agent. When the solubility of the activeingredient increases at the basic side, the pH of the solution is raisedby adding the alkaline agent in an amount more than equivalent to theacidic agent. In either case, the pH near the acidic agent immediatelyafter the dissolution is low, while the pH near an alkaline agent ishigh. In a case where the solubility of an active ingredient does notdepend on pH, the ratio of an acidic agent and an alkaline agent can beoptionally selected.

The amount of carbon dioxide precursor, i.e. alkaline agent, to beincorporated is proportional to the volume of carbon dioxide gasgenerated. When it is desired to increase the dissolution rate of anactive ingredient included in a formulation containing effervescentgranules, it can be advantageous to increase the amount of carbondioxide precursor accordingly, and the amount is usually selected fromthe range of from about 3% to about 70%, preferably from about 10% to70% by weight based on the effervescent granule.

An acidic agent and a carbon dioxide precursor are used respectively ina powdery or granular state, usually 90% or more of them being capableof passing through a 100 mesh (150 μ) screen. The particle size of thebinder used will usually be about 100 mesh (150 μ). In any case, it isgenerally acceptable that the additional amount of either component canremain unreacted.

As used herein, the term “hot-melt extrudable” refers to a compound orformulation that can be hot-melt extruded. A hot-melt extrudable binderis one that is sufficiently rigid at standard ambient temperature andpressure but is capable of deformation or forming a semi-liquid stateunder elevated heat or pressure. Although the formulation of theinvention need not contain a plasticizer to render it hot-meltextrudable, plasticizers of the type described herein can be included.

Examples of hot-melt extrudable binders which can be used in theeffervescent granules include acacia, tragacanth, gelatin, starch,cellulose materials such as methyl cellulose and sodium carboxy methylcellulose, alginic acids and salts thereof, polyethylene glycol, guargum, polysaccharide, bentonites, sugars, invert sugars, poloxamers(PLURONIC F68, PLURONIC F127), collagen, albumin, gelatin, cellulosicsin nonaqueous solvents, and combinations of the above and the like.Other binders include, for example, polypropylene glycol,polyoxyethylene-polypropylene copolymer, polyethylene ester,polyethylene sorbitan ester, polyethylene oxide and the like.

Binders may be used in an amount of up to about 60 weight percent andpreferably about 3 to about 8 weight percent of the total composition.All binders used in this invention are hot-melt extrudable. While themelting and/or softening point temperatures of these binders usuallyrise with increase of their molecular weights, preferable ones are thosewith a melting or softening point temperature less than about 150° C.However, binders having melting or softening points greater than about150° C. can be used. Hot-melt extrudable binders having a melting orsoftening point temperature greater than about 150° C. will require useof a plasticizer during hot-melt extrusion such that the binder meltingor softening point temperature will be lowered below 150° C. Among theabove-mentioned binders, polyethylene glycol is preferable, and thathaving a molecular weight of about 1000 to 8000 Da is more preferable.

The binder can be used in any form such as powder, granules, flakes orheat-molten liquid. While the amount of binder to be added can bemodified, it is usually present in an amount less than about 10% byweight and preferably in the range of about 3-8% by weight of thegranule.

By “controllable rate of effervescence” is meant that the rate ofeffervescence can be controlled such that either a rapid, intermediateor slow rate of effervescence by an effervescent granule is achieved.The rate of effervescence by an effervescent granule is controlled asdetailed below.

When referring to the rate of effervescence as “rapid”, it is understoodthat the effervescent granules of the present invention shoulddisintegrate in an aqueous solution in less than 10 minutes, anddesirably between about 15 seconds and about 7 minutes. In aparticularly preferred embodiment according to the present invention,the effervescent granules should dissolve in an aqueous solution inbetween about 8 seconds and about 5 minutes. Disintegration time can beapproximated by observing the disintegration time of the effervescentgranules immersed in water at about 37° C. The disintegration time isthe time from immersion to substantially complete the effervescentgranules as determined by visual observation. As used in this disclosurethe term “complete disintegration” of the effervescent granules refersto the dissolution or disintegration of the effervescent granules.Disintegration times referred to in this-disclosure should be understoodas determined by the method used herein unless otherwise specified.

When referring to the rate of effervescence as “intermediate,” it isunderstood that the effervescent granules of the invention shoulddisintegrate in an aqueous solution in more than about 10 minutes andless than about 1 hour.

When referring to the rate of effervescence as “slow,” it is understoodthat the effervescent granules of the present invention shoulddisintegrate in an aqueous solution in about 1 hour to about 4 hours.

Control of the rate of effervescence can be achieved by varying therelative amounts of the components in the effervescent granule. Thus, byincreasing the amount of hot-melt extrudable binder relative to thetotal weight of the effervescent granule, a less friable and strongergranule can be generally prepared. Conversely, by decreasing the amountof hot-melt extrudable binder relative to the total weight of theeffervescent granule, a more friable or weaker granule can be generallyprepared. Hydrophobic binders will generally tend to have a greaterimpact upon granule hardness than hydrophilic binders.

Generally, forming a eutectic mixture between the acidic agent and thehot-melt extrudable binder before hot-melting extruding with thealkaline agent will yield effervescent granules that are harder and thusslower dissolving than those prepared by hot-melt extruding the binder,acidic agent and alkaline agent components together simultaneously.

Having an excess of either the acidic agent or alkaline agent in theeffervescent granule will generally result in increased rate ofeffervescence when compared to an effervescent granule having the sameamounts, on an equivalent basis, of both agents. Regardless of whethereither agent is in excess, the total amount of gas produced by aneffervescent granule will not exceed the theoretical amount of gasproduced by the agent serving as the limiting reagent.

It is possible that including a plasticizer in the present effervescentgranules will alter its rate of effervescence. Generally, increasing theamount of plasticizer present will increase or prolong the time ofeffervescence.

The rate of effervescence can also be controlled by varying thehydrophilicity or hydrophobicity of the hot-melt extrudable binder.Generally, the more hydrophobic the binder, the slower the rate ofeffervescence. The solubility and rate of dissolution of a hydrophobicbinder are important factors to consider as the level of binder in theeffervescent granule is increased. For example, one can prepare aneffervescent granule having a rapid rate of effervescence by a watersoluble hot-melt extrudable binder such as an electrolyte ornonelectrolyte such as xylitol, which can form a eutectic mixture withan appropriate acidic agent during hot-melt extrusion.

Conversely, one can prepare an effervescent granule having a slow rateof effervescence by employing a poorly water soluble hot-melt extrudablebinder such as hydrogenated castor oil, lipids, wax, cholesterol, fattyacids or mono-, di- or triglycerides. Additionally, an effervescentgranule having an intermediate rate of effervescence can be prepared byemploying a binder, or combination of binders, such as those justdiscussed and optionally a surface active agent or cosolvent thatimproves wetting or disintegration of the effervescent granule.

Thus, rate of effervescence of the effervescent granule can becontrolled by: (1) varying the relative amounts of the components; (2)optionally forming a eutectic mixture between the acidic agent andhot-melt extrudable binder; (3) varying acidic agent: alkaline agentratio; (4) hydrophilicity vs. hydrophobicity of hot-melt extrudablebinder; (5) varying the effervescent couple: hot-melt extrudable binderratio; and (6) varying the amount of plasticizer present.

It should also be noted that when the effervescent granules are includedin a tablet form, the hardness of a tablet may also play a role indisintegration time. Specifically, increasing the hardness of a tabletcan increase the disintegration time just as decreasing hardness maydecrease disintegration time. The hardness of the tablet can becontrolled by the pressure used on the punches to compress theeffervescent granule-containing formulation and by the amount ofeffervescent granules, concentration of effervescent couple, and amountsof drug and other excipients present in the tablet composition.

The effervescent granules of the invention can be included informulations containing active ingredients and particularlypharmacologically active agents. As used herein, the term “activeingredient” means a therapeutic compound, a flavoring agent, asweetening agent, a vitamin, cleansing agent and other such compoundsfor pharmaceutical, veterinary, horticultural, household, food,culinary, pesticidal, agricultural, cosmetic, herbicidal, industrial,cleansing, confectionery and flavoring applications. When theeffervescent granules are formulated into tablets, such tablets can alsocontain coloring agents, non-effervescent disintegrants, lubricants andthe like. The effervescent granules of the invention can be formulatedin a variety of forms such as a tablet, capsule, suspension,reconstitutable powder and suppository.

When a formulation including the effervescent granules and a therapeuticcompound is included in a pharmaceutical tablet, the tablet's size andshape can be adapted for direct oral administration to a patient, suchas a human patient. The pharmaceutical tablet is substantiallycompletely disintegrable upon exposure to water and/or saliva. Theeffervescent granule is present in an amount effective to aid indisintegration of the tablet, and to provide a distinct sensation ofeffervescence when the tablet is placed in the mouth of a patient.

The effervescent sensation is not only pleasant to the patient but alsotends to stimulate saliva production, thereby providing additional waterto aid in further effervescent action. The patient should be able toperceive a distinct sensation of “fizzing” or bubbling as the tabletdisintegrates in the mouth. To provide this sensation, the amount ofeffervescent granule in each tablet desirably is arranged to provideabout 20 to about 60 cm³ of gas. The “fizzing” sensation substantiallyenhances the organoleptic effects of the tablet. Thus, the amount ofeffervescent granule useful in accordance with the present invention isalso an amount effective to provide a positive organoleptic sensation toa patient. A “positive” organoleptic sensation is one which is pleasantor enjoyable and which can be perceived readily by a normal human being.Thus, once the tablet is placed in the patient's mouth, it willdisintegrate substantially completely without any voluntary action bythe patient. Even if the patient does not chew the tablet,disintegration will proceed. Upon disintegration of the tablet, thetherapeutic compound, which itself can be particulate, is released andcan be swallowed as a slurry or suspension.

The mass of each such pharmaceutical tablet generally should be lessthan about 2.0 g and preferably less than about 0.5 g. The tablet mayinclude surface markings, cuttings, grooves, letters and or numerals forthe purpose of decoration and/or identification. Preferably, the tabletis a compressed tablet. It includes effervescent granules, together witha therapeutic compound and other components. The size of the tablet isalso dependent upon the amount of material used. Circular, disk-liketablets desirably have diameters of about {fraction (11/16)} inch orless, whereas elongated tablets desirably have a long dimension of about⅞ inch or less.

The amount of effervescent granules of the present invention useful forthe formation of tablets, in general, according to the present inventionshould range from about 2 to about 90% by weight of the final tabletcomposition, and preferably between about 5 and about 40% by weightthereof. In a more preferred embodiment, the amount of effervescentgranule according to the present invention ranges from between about 3and about 8% by weight of the final tablet composition.

Non-effervescent disintegrants include starches such as corn starch,potato starch, pregelatinized and modified starches thereof, sweeteners,clays, such as bentonite, micro-crystalline cellulose, alginates, sodiumstarch glycolate, gums such as agar, guar, locust bean, karaya, pecitinand tragacanth. Disintegrants can comprise up to about 20 weight percentand preferably between about 2 and about 10 percent of the total weightof the composition.

Coloring agents can include titanium dioxide, and dyes suitable for foodsuch as those known as F.D. & C. dyes and natural coloring agents suchas grape skin extract, beet red powder, beta-carotene, annato, carmine,turmeric, paprika, etc. The amount of coloring used can range from about0.1 to about 3.5 weight percent of the total composition.

Flavors incorporated in the composition may be chosen from syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereofThese may include cinnamon oil, oil of wintergreen, peppermint oils,clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil,oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Alsouseful as flavors are vanilla, citrus oil, including lemon, orange,grape, lime and grapefruit, and fruit essences, including apple pear,peach, strawberry, raspberry, cherry, plum, pineapple, apricot and soforth. Flavors which have been found to be particularly useful includecommercially available orange, grape, cherry and bubble gum flavors andmixtures thereof. The amount of flavoring may depend on a number offactors, including the organoleptic effect desired. Flavors may bepresent in an amount ranging from about 0.5 to about 3.0 by weight basedupon the weight of the composition. Particularly preferred flavors arethe grape and cherry flavors and citrus flavors such as orange.

Tablets according to this aspect of the present invention can bemanufactured by well-known tableting procedures. In common tabletingprocesses, material which is to be tableted is deposited into a cavity,and one or more punch members are then advanced into the cavity andbrought into intimate contact with the material to be pressed, whereuponcompressive force is applied. The material is thus forced intoconformity with the shape of the punches and the cavity. Varioustableting methods are well known to those skilled in the art and notdetailed herein.

Materials to be incorporated in the tablets, other than the therapeuticcompound and the effervescent granule can, be pretreated to formgranules that readily lend themselves to tableting. This process isknown as granulation. As commonly defined, “granulation” is any processof size enlargement whereby small particles are gathered together intolarger, permanent aggregates to yield a free-flowing composition havinga consistency suitable for tableting. Such granulated compositions mayhave consistency similar to that of dry sand. Granulation may beaccomplished by agitation in mixing equipment or by compaction,extrusion or globulation.

As noted in Chapter 6 of Pharmaceutical Dosage Forms, supra, lubricantsnormally are used in manufacture of effervescent tablets. Without theuse of an effective lubricant, tableting by use of high speed equipmentwould be difficult. Effervescent granulations are inherently difficultto lubricate due to both the nature of the raw materials and therequirement that the tablets disintegrate rapidly.

Lubricant, as used herein, means a material which can reduce thefriction arising at the interface of the tablet and the die wall duringcompression and ejection thereof. Lubricants may also serve to preventsticking to the punch and, to a lesser extent, the die wall as well. Theterm “antiadherents” is sometimes used to refer specifically tosubstances which function during ejection. As used in the presentdisclosure, however, the term “lubricant” is used generically andincludes “antiadherents”. Tablet sticking during formation and/orejection may pose serious production problems such as reducedefficiency, irregularly formed tablets, and non-uniform distribution ofintended agents or ingredients to be delivered thereby. These problemsare particularly severe with high speed tableting approaches andmethods.

Lubricants may be intrinsic or extrinsic. A lubricant which is directlyapplied to the tableting tool surface in the form of a film, as byspraying onto the die cavity and/or punch surfaces, is known as anextrinsic lubricant. Although extrinsic lubricants can provide effectivelubrication, their use requires complex application equipment andmethods which add cost and reduce productivity.

Intrinsic lubricants are incorporated in the material to be tableted.Magnesium, calcium and zinc salts of stearic acid have long beenregarded as the most efficient intrinsic lubricants in common use.Concentrations of two percent or less are usually effective.

Other traditional intrinsic lubricants include hydrogenated andpartially hydrogenated vegetable oils, animal fats, polyethyleneglycol,polyoxyethylene monostearate, talc, light mineral oils, sodium benzoate,sodium lauryl sulphate, magnesium oxide and the like. See EuropeanPatent Application No. 0,275,834, the disclosure of which isincorporated by reference. See also Leal, et al., U.S. Pat. No.3,042,531.

Lubricants, according to the present invention, can be used in an amountof up to 1.5 weight percent and preferably between about 0.25 and about1.0 weight percent of the total composition.

Intrinsic lubricants pose certain serious difficulties when used inconventional tablets. Many lubricants materially retard thedisintegration of non-effervescent tablets. However, the effervescentgranules used in the dosage form of the present invention overcome anysuch retardation. In dissolution of conventional effervescent tablets,the lubricant may cause “scumming” and/or agglomeration. Stearates, forexample leave an objectionable “scum” when an effervescent tablet isplaced in a glass of water. This “scum” reduces the aesthetic appeal ofthe solution made from an effervescent dosage form. However, because thetablets of the present invention dissolve in the mouth, the solution isnever seen by the user. Therefore, the propensity of a lubricant to“scum” is of less importance. Thus, lubricants which can causedissolution or scumming problems in other dosage forms can be used indosage forms according to the present invention without material adverseeffect.

The therapeutic compound included in a dosage form including theeffervescent granules according to the invention can include at leastone psychotropic drug such as a sedative, antidepressant, neuroleptic,or hypnotic. The present invention is especially valuable withpsychotropic drugs in that a patient receiving such drugs, particularlya patient in a mental institution, often attempts to hold a conventionalpharmaceutical tablet or capsule concealed within his mouth rather thanswallow it. The patient may then surreptitiously remove the tablet orcapsule when medical personnel are not present. The preferred dosageforms according to this aspect of the present invention aresubstantially resistant to such concealment, inasmuch as they willdisintegrate rapidly even if they are concealed within the mouth.

As the therapeutic compound, use can be of synthetic antibacterialagents of hardly water-soluble pyridone-carboxylic acid type such asbenofloxacin, nalidixic acid, enoxacin, ofloxacin, amifloxacin,flumequine, tosfloxacin, piromidic acid, pipemidic acid, miloxacin,oxolinic acid, cinoxacin, norfloxacin, ciprofloxacin, pefloxacin,lomefloxacin, enrofloxacin, danofloxacin, binfloxacin, sarafloxacin,ibafloxacin, difloxacin and salts thereof. Other therapeutic compoundswhich can be formulated along with the effervescent granules into aneffervescent solid dosage form include penicillin, tetracycline,erythromycin, cephalosporins and other antibiotics.

The therapeutic compounds which can be formulated in suitable dosageforms along with the effervescent granules of the invention also includeantibacterial substances, antihistamines and decongestants,anti-inflammatories, antiparasitics, antivirals, anxiolytic agents,morphine derivatives, serotonin agonists, levorotatory isomers ofthyroxine, cholesterol lowering agents, alpha adrenergic blockingagents, local anesthetics, antifungal, amoebicidal, or trichomonocidalagents, analgesics, antiarthritics, antiasthmatics, anticoagulants,anticonvulsants, antidepressants, antidiabetics, antineoplastics,antipsychotics, antihypertensives, phenanthrene derivatives,antidiarrheal agents, diuretics, and muscle relaxants.

Representative antibacterial substances are beta-lactam antibiotics,tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin,sulfonamides, aminoglycoside antibiotics, tobramycin, nitrofurazone,nalidixic acid and analogs and the antimicrobial combination offludalanine/pentizidone. A representative phenanthrene derivative ismorphine sulfate. A representative antidiarrheal agent is loperamidehydrochloride. A representative anxiolytic agent is buspirone. Arepresentative diuretic agent is hydrochlorthiazide. A representativemorphine derivative is hydromorphone hydrochloride. Representativeantihistamines and decongestants are perilamine, chlorpheniramine,tetrahydrozoline and antazoline. Representative anti-inflammatory drugsare cortisone, hydrocortisone, betamethasone, dexamethasone,fluocortolone, prednisolone, triamcinolone, indomethacin, sulindac andits salts and corresponding sulfide. A representative antiparasiticcompound is ivermectin. Representative antiviral compounds are acyclovirand interferon. Representative analgesic drugs are diflunisal, aspirinor acetaminophen.

Representative antiarthritics are phenylbutazone, indomethacin,silindac, its salts and corresponding sulfide, dexamethasone, ibuprofen,allopurinol, oxyphenbutazone or probenecid. Representative antiasthmadrugs are theophylline, ephedrine, beclomethasone dipropionate andepinephrine. Representative anticoagulants are heparin,bishydroxycoumarin, and warfarin. Representative anticonvulsants arediphenylhydantoin and diazepam. Representative antidepressants areamitriptyline, chlordiazepoxide perphenazine, fluoxetine hydrochloride,protriptyline, imipramine and doxepin. A representative cholesterollowering agent is simvastatin. A representative alpha adrenergicblocking agent is ergotamine tartrate. A representative serotoninagonist is sumatropin succinate. A representative levorotatory isomer ofthyroxine is levothyroxine sodium. Representative antidiabetics areinsulin, somatostatin and its analogs, tolbutamide, tolazamide,acetchexamide and chlorpropamide. Representative antineoplastics areadriamycin, fluorouracil, methotrexate and asparaginase. Representativeantipsychotics are prochlorperazine, lithium carbonate, lithium citrate,thioridazine, molindone, fluphenazine, trifluoperazine, perphenazine,amitriptyline and trifluopromazine. Representative antihypertensives arespironolactone, methyldopa, hydralazine, clonidine, chlorothiazide,deserpidine, timolol, propranolol, metoprolol, prazosin hydrochlorideand reserpine. Representative muscle relaxants aresuccinylcholine-chloride, danbrolene, cyclobenzaprine, methocarbamol anddiazepam.

The therapeutic compound(s) contained within a formulation containingeffervescent granules can be formulated as its pharmaceuticallyacceptable salts. As used herein, “pharmaceutically acceptable salts”refer to derivatives of the disclosed compounds wherein the parentpharmacologically active compound is modified by making acid or basesalts thereof. Examples of pharmaceutically acceptable salts include,but are not limited to, mineral or organic acid salts of basic residuessuch as amines; alkali or organic salts of acidic residues such ascarboxylic acids; and the like. The pharmaceutically acceptable saltsinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and thelike; and the salts prepared from organic acids such as amino acids,acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutarnic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, furnaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent therapeutic compound which contains a basicor acidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a predetermined amount of the appropriate base or acid inwater or in an organic solvent, or in a mixture of the two. Generally,nonaqueous media are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used in this disclosure, the term vitamin refers to trace organicsubstances that are required in the diet. For the purposes of thepresent invention, the term vitamin(s) include, without limitation,thiamine riboflavin, nicotinic acid, pantothenic acid, pyridoxine,biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A,vitamin D, vitamin E and vitamin K. Also included within the termvitamin are the coenzymes thereof. Coenzymes are specific chemical formsof vitamins. Coenzymes include thiamine pyrophosphates (TPP), flavinmononucleotide (FMM), flavin adenine dinucleotive (FAD), Nicotinamideadenine dinucleotide (AND), Nicotinamide adenine dinucleotide phosphate(NADP) Coenzyme A (CoA) pyridoxal phosphate, biocytin, tetrahydrofolicacid, coenzyme B12, lipoyllysine, 11-cis-retinal, and1,25-dihydroxycholecalciferol. The term vitamin(s) also includescholine, carnitine, and alpha, beta, and gamma carotenes.

As used in this disclosure, the term “mineral” refers to inorganicsubstances, metals, and the like required in the human diet. Thus, theterm “mineral” as used herein includes, without limitation, calcium,iron, zinc, selenium, copper, iodine, magnesium, phosphorus, chromiumand the like, and mixtures thereof

The term “dietary supplement” as used herein means a substance which hasan appreciable nutritional effect when administered in small amounts.Dietary supplements include, without limitation, such ingredients as beepollen, bran, wheat germ, kelp, cod liver oil, ginseng, and fish oils,amino-acids, proteins and mixtures thereof. As will be appreciated,dietary supplements may incorporate vitamins and minerals.

The amount of therapeutic compound incorporated in each tablet may beselected according to known principles of pharmacy. An effective amountof therapeutic compound is specifically contemplated. By the termeffective amount, it is understood that, with respect to for examplepharmaceuticals, a pharmaceutically effective amount is contemplated. Apharmaceutically effective amount is the amount or quantity of a drug orpharmaceutically active substance which is sufficient to elicit therequired or desired therapeutic response, or in other words, the amountwhich is sufficient to elicit an appreciable biological response whenadministered to a patient. As used with reference to a vitamin ormineral, the term “effective amount” means an amount at least about 10%of the United States Recommended Daily Allowance (“RDA”) of thatparticular ingredient for a patient. For example, if an intendedingredient is vitamin C, then an effective amount of vitamin C wouldinclude an amount of vitamin C sufficient to provide 10% or more of theRDA. Typically, where the tablet includes a mineral or vitamin, it willincorporate higher amounts, preferably about 100% or more of theapplicable RDA.

The therapeutic compound is used in finely divided form, i.e. powder orgranulate so as to increase the dissolution rate. It is preferable touse a finely powdered therapeutic compound to increase the dissolutionrate, more preferably, the therapeutic compound being capable ofallowing not less than 80%, desirably not less than 90% of it to passthrough a 100 mesh (150 mu m) screen. The amount of therapeutic compoundto be incorporated ranges usually from about 0.1 to 50%, preferablyabout 1 to 25% by weight based on the effervescent composition, and theratio may be suitably modified depending on the therapeutic compoundthen employed. When the therapeutic compound is an acid substancecapable of effervescing by reaction with carbonate, the therapeuticcompound itself may be used as the acidic agent, and, in this case, anacidic agent for use as set forth below may be optionally added further.

When the effervescent granules of the invention are formulated into areconstitutable powder for a carbonated beverage, they can be preparedaccording to Example 4 or other suitable method known to those of skillin the art.

The effervescent granules formulated into a suppository can be used totreat vaginal infection and adjust vaginal pH. Such a formulation can beprepared according to example 5, or other method well known to those ofskill in the art.

Suspensions containing the effervescent granules of the invention and aherbicide can be used in agricultural applications. Such formulationscan comprise a reconstitute powder according to example 6, which issuspended in a liquid prior to use.

Hot Melt Extrusion

In one aspect of this invention, the effervescent granule is produced bya hot-melt extrusion method as described herein. An acidic agent and analkaline agent, preferably a carbon dioxide precursor, and a hot-meltextrudable binder, all in a dry state, are placed into a mixer or hopperand agitated (blended) until thoroughly mixed to form an effervescentmixture. The effervescent mixture is then hot-melt extruded at a rateand temperature sufficient to melt or soften the binder, to minimizedegradation of the components and to form an extrudant which issubsequently ground or chopped into effervescent granules.

In another aspect of the invention, the effervescent granule is producedby a hot melt extrusion process as follows. An acidic agent and ahot-melt extrudable binder, capable of forming a eutectic mixture withthe acidic agent, are placed into a mixer and agitated until thoroughlymixed to form a mixture which is hot-melt extruded and ground to form agranular eutectic mixture. An alkaline agent, such as a carbon dioxideprecursor, is added to the granular eutectic mixture and thoroughlyblended to form an effervescent mixture. The effervescent mixture isthen hot-melt extruded at a rate and temperature sufficient to melt orsoften the eutectic mixture, to minimize degradation of the components,e.g. degradation of NaHCO₃ to Na₂CO₃, and to form an extrudant which issubsequently ground or chopped into effervescent granules.

As used herein, the term “effervescent mixture” means a granular orparticulate mixture comprising an acidic agent, an alkaline agent and ahot-melt extrudable binder which when placed in water will causeeffervescence. As used herein, the term “eutectic mixture” means amixture of an acidic agent and a hot-melt extrudable binder that hasbeen hot-melt extruded and that melts or softens at a temperature lowerthan the melting or softening temperature of the hot-melt extrudablebinder neat. The eutectic mixture can be a full or partial mixture andcan be referred to as a “solid solution.”

The rate at which the hot-melt extrusion is conducted can also varywidely. The rate will be such that degradation of the components of themixture being extruded will be minimized. Such rate can be easilydetermined experimentally and will vary according to the particularmixture being extruded. Generally, the extrusion rate is such that thetime of exposure of the components to the elevated temperature is lessthan 5 minutes and preferably less than 2 minutes.

The rate of effervescence can be controlled by varying the rate ofhot-melt extrusion. Generally, increasing the rate of hot-melt extrusionof the effervescent granule will increase the rate of effervescence.This is especially true for hot-melt extrudable binders having meltingor softening points greater than about 100 C. Conversely, decreasing therate of hot-melt extrusion of effervescent granule will generallydecrease the rate of effervescence.

The hot-melt extrusion process preferably employed is conducted at anelevated temperature, i.e. the heating zone(s) of the extruder is aboveroom temperature (about 20° C.). It is important to select an operatingtemperature range that will minimize the degradation or decomposition ofthe effervescent composition during processing. The operatingtemperature range is generally in the range of from about 50° C. toabout 150° C. as determined by the setting for the extruder heatingzone(s). The temperature of the mixture being hot-melt extruded will notexceed 150° C. and preferably will not exceed 120° C. The hot-meltextrusion is conducted employing a dry granular or powdered feed.

The extruder used to practice the invention can be any such commerciallyavailable model equipped to handle dry feed and having a solid conveyingzone, one or multiple heating zones, and an extrusion die. A two stagesingle screw extruder, such as that manufactured by BRABENDER or KILLIONare two such apparati. It is particularly advantageous for the extruderto possess multiple separate temperature controllable heating zones.

Many conditions can be varied during the extrusion process to arrive ata particularly advantageous formulation. Such conditions include, by wayof example, formulation composition, feed rate, operating temperature,extruder screw RPM, residence time, die configuration, heating zonelength and extruder torque and/or pressure. Methods for the optimizationof such conditions are known to the skilled artisan.

When higher melting temperature, higher molecular weight or highsoftening temperature binders are employed, the hot-melt extrusion mayrequire higher processing temperature, pressure and/or torque than whenbinders having a lower molecular weight, melting or softeningtemperature are employed. By including a plasticizer, and, optionally,an antioxidant, in a formulation, processing temperature, pressureand/or torque may be reduced. Plasticizers are not required in order topractice the invention. Their addition to the formulation iscontemplated as being within the scope of the invention. Plasticizersare advantageously included in the effervescent granules when hot-meltextrudable binders having a melting or softening point temperaturegreater than 150° C. are employed.

As used herein, the term “plasticizer” includes all compounds capable ofplasticizing the hot-melt extrudable binder of the invention. Theplasticizer should be able to lower the melting temperature or glasstransition temperature (softening point temperature) of the hot-meltextrudable binder. Plasticizers, such as low molecular weight PEG,generally broaden the average molecular weight of the hot-meltextrudable binder thereby lowering its glass transition temperature orsoftening point. Plasticizers also generally reduce the viscosity of apolymer melt thereby allowing for lower processing temperature andextruder torque during hot-melt extrusion. It is possible theplasticizer will impart some particularly advantageous physicalproperties to the effervescent granules.

Plasticizers useful in the invention can include, by way of example andwithout limitation, low molecular weight polymers, oligomers,copolymers, oils, small organic molecules, low molecular weight polyolshaving aliphatic hydroxyls, ester-type plasticizers, glycol ethers,poly(propylene glycol), multi-block polymers, single block polymers, lowmolecular weight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol and glycerin.

Such plasticizers can also be ethylene glycol, 1,2-butylene glycol,2,3-butylene glycol, styrene glycol, diethylene glycol, triethyleneglycol, tetraethylene glycol and other poly(ethylene glycol) compounds,monopropylene glycol monoisopropyl ether, propylene glycol monoethylether, ethylene glycol monoethyl ether, diethylene glycol monoethylether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate,dibutylsebacate, acetyltributylcitrate, triethyl citrate, acetyltriethyl citrate, tributyl citrate and allyl glycolate. All suchplasticizers are commercially available from sources such as Aldrich orSigma Chemical Co.

It is contemplated and within the scope of the invention, that acombination of plasticizers may be used in the present formulation. Oneadvantageous combination is that comprised of poly(ethylene glycol) andlow molecular weight poly(ethylene oxide). The PEG based plasticizersare available commercially or may be made by a variety of methods, suchas disclosed in Poly(ethylene glycol)Chemistry: Biotechnical andBiomedical Applications (J. M. Harris, Ed.; Plenum Press, NY) theteachings of which are hereby incorporated by reference.

The amount of plasticizer used in the effervescent granules will dependupon its composition, physical properties, effect upon the effervescentgranules, interaction with other components of the granules and othersuch reasons. Generally, the plasticizer content will not exceed about40% wt. of the formulation.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

One embodiment of the present invention provides an effervescent granulehaving a controllable rate of effervescence comprising:

a hot-melt extrudable binder present in the amount of about 3% to about8% by weight of said effervescent granule, said binder being capable offorming a eutectic mixture with an acidic agent;

an acidic agent; and

an alkaline agent; said effervescent granule being made by a processcomprising:

dry blending and hot-melt extruding said acidic agent and said hot-meltextrudable binder to form an acidic mixture; and

dry blending and hot-melt extruding the acidic mixture and said alkalineagent to form said effervescent granule.

Another embodiment of the present invention provides a hot-meltextrusion process for preparing an effervescent granule having acontrollable rate of effervescence, said process comprising:

dry blending and hot-melt extruding an acidic agent, a hot-meltextrudable binder and a plasticizer to form a eutectic mixture; and

dry blending and hot-melt extruding the eutectic mixture and an alkalineagent to form said effervescent granule.

The foregoing will be better understood with reference to the followingexamples which detail certain procedures for the manufacture of tabletsaccording to the present invention. All references made to theseexamples are for the purposes of illustration. They are not to beconsidered limiting as to the scope and nature of the present invention.

EXAMPLE 1 Effervescent Granule Formulation (MS-EGF) Prepared by hot MeltExtrusion

The present example is provided to demonstrate the utility of thepresent invention for the preparation of a fast melt tablet formulationthat included one or more narcotics. Morphine sulfate is the example ofthe narcotic provided as part of the present example. As will beunderstood by those of ordinary skill in the art, components that arereasonably equivalent to these for purposes of pharmaceutical agentpreparation may be used in substitution of the specifically developedingredients below.

Ingredient Amount (% Wt.) Morphine Sulfate 24 Sodium Bicarbonate 27Citric Acid, Anhydrous 27 Microcrystalline Cellulose 10 Xylitol 10Sucrose Stearate 2

Category B

Morphine Sulfate Tablet Foundation

Formulation 1:

Ingredient Amount (% Wt.) MS-EGF (30-60 mesh) 50 MicrocrystallineCellulose 31 Mannitol 10 AcDiSol 5 Aspartame 3 Redberry Flavor 0.4Magnesium Stearate 0.5 Cab-O-Sil M5P 0.1

Formulation 2:

Ingredient Amount (% Wt.) MS-EFG (30-60 mesh) 50 MicrocrystallineCellulose 31 Mannitol 10 L-HPC LH-11 5 Aspartame 3 Redberry flavor 0.4Magnesium Stearate 0.5 Cab-O-Sil M5P 0.1

Formulation 3:

Ingredient Amount (% Wt.) MS-EFG (20-80 mesh) 50 Anhydrous Lactose 18Fujicalin SG 18 L-HPC LH-11 3 Aspartame 0.3 Natural Orange Powder 0.3Magnesium Stearate 0.6 Fumed Silicon Dioxide 0.1

The morphine sulfate in the effervescent granulation formulation isdried at 100° C. for 2-4 hours to reduce the moisture content of thematerial. Other ingredients are dried at 40°60° C. to significantlyreduce the moisture content of the material.

The ingredients in Category A were then blended for 10 minutes andextruded in a hot melt extruder at 70°-100° C. to soften and melt thethermal binders (sucrose stearate and xylitol) and to form granulescontaining the effervescent couple.

Granules were then screened and blended with the ingredients in CategoryB for 5 minutes prior to compression. Morphine sulfate tablets fromFormulations #1, #2 or #3 are then compressed to a hardness ofapproximately 1-5 kg and tablets disintegrate in water in approximately15-35 seconds. Tablet size, hardness and disintegration times will varywith slight modifications in the formulation. The dose of the morphinesulfate may be varied by varying the amount and/or form of the drug tobe included in the formulation.

EXAMPLE 2 Loperamide HCl Fast Melt Tablet Formulation

The present example is provided to demonstrate the utility of thepresent invention for the preparation of formulations useful in treatinggastrointestinal disorders, such as diarrhea. Loperamide HCl is employedin the present example, and is only one of many potential agents thatmay be used.

Category A

Effervescent Granule Formulation (LH-EGF)

Prepared by Hot Melt Extrusion

Ingredient Amount (% Wt.) Loperamide Hydrochloride 5 Sodium Bicarbonate27 Citric Acid Anhydrous 27 Tartaric Acid 3 Microcrystalline Cellulose15 Anhydrous Lactose 8 Xylitol 12 Crodesta F160 3

Category B

Loperamide Hydrochloride Tablet Formulation

Ingredient Amount (% Wt.) LH-EFG (30-80 mesh) 50 MicrocrystallineCellulose 31 Mannitol 8 AcDiSol 5 L-HPC LH-11 2 Aspartame 3 RedberryFlavor 0.4 Magnesium Stearate 0.5 Cab-O-Sil M5P 0.1

The ingredients in Category A are dried at elevated temperature in thepresence of a dessicant to significantly reduce the moisture content ofeach material.

The ingredients are then blended for 10 minutes and extruded in a hotmelt extruder at 70°-100° C. to soften and melt the thermal binders(sucrose stearate and xylitol) to form granules containing theeffervescent couple.

Granules are passed through a screen and then blended with theingredients in Category B for 5 minutes prior to compression. LoperamideFICI tablets are then compressed to a hardness of approximately 1-3 kgand tablets disintegrate in purified water in approximately 15-35seconds.

EXAMPLE 3 Acyclovir (200 mg) Antiviral Fast Melt Tablets

The present example is provided to demonstrate the utility of thepresent invention for the preparation of antiviral formulations.Acyclovir is employed in the present example and is only one of thetherapeutic agents which can be formulated in suitable dosage formsalong with the effervescent granules of the invention.

Category A

Effervescent Granule Formulation (ACY-EFG)

Prepared by Hot Melt Extrusion

Ingredient Amount (% Wt.) Acyclovir 50 Sodium Bicarbonate 18 Citric AcidAnhydrous 18 Anhydrous Lactose 7 Xylitol 5 Crodesta F160 2

Category B

Acyclovir Tablet Formulation

Ingredient Amount (% Wt.) ACY-EFG (30-60 mesh) 50 MicrocrystallineCellulose 18 Fujicalin SG 18 L-HPC LH-11 10 Aspartame 3 Redberry Flavor0.4 Magnesium Stearate 0.5 Cab-O-Sil M5P 0.1

The ingredients in Category A are dried to significantly reduce themoisture content of each material.

The ingredients are then blended for 10 minutes and extruded in a hotmelt extruder at 70°-100° C. to soften and melt the thermal binders(sucrose stearate and xylitol) to form granules containing theeffervescent couple.

Granules are then screened and blended with the ingredients in CategoryB for 5 minutes prior to compression. Acyclovir tablets are thencompressed to a hardness of approximately 1-3 kg and tabletsdisintegrate in water in approximately 20-45 seconds.

EXAMPLE4 Buspirone (5 mg) Anxiolytic Fast Melt Tablets

The present example is provided to demonstrate the utility of thepresent invention for the preparation of hydrochloride formulationsuseful in treating mild anxiety disorders. Buspirone is employed in thepresent example, such drug being characterized by its tendency againstinducing significant tolerance or psychological dependence.

Category A

Effervescent Granule Formulation (BUS-EGF)

Prepared by Hot Melt Extrusion

Ingredient Amount (% Wt.) Buspirone 8 Sodium Bicarbonate 25 Citric AcidAnhydrous 25 Avicel PH113 12 Anhydrous Lactose 17 Xylitol 11 CrodestaF160 2

Category B

Buspirone Tablet Formulation

Ingredient Amount (% Wt.) BUS-EGF (20-80 mesh) 50 MicrocrystallineCellulose (Avicel PH113) 31 Mannitol (Mannogen 3215) 10 AcDiSol 5Aspartame 3 Redberry Flavor 0.4 Magnesium Stearate 0.5 Fumed SiliconDioxide 0.1

Ingredients in Category A are dried at 40°-60° C. to significantlyreduce the moisture content of each material.

The ingredients in Category A were then blended for 10 minutes andextruded in a hot melt extruder at 70°-100° C. to soften and melt thethermal binders (sucrose stearate and xylitol) and to form granulescontaining the effervescent couple.

Granules were then screened and blended with the ingredients in CategoryB for 5 minutes prior to compression. Buspirone tablets were thencompressed to a hardness of approximately 1-3 kg and tabletsdisintegrate in water in approximately 15-35 seconds.

EXAMPLE 5 Hydrochlorthiazide (25 mg) Fast Melt Tablets-diuretic

The present example is provided to demonstrate the utility of thepresent invention for the preparation of diuretic formulations useful intreating hypertension. Hydrochlorthiazide is the therapeutic drugemployed in the present example.

Category A

Effervescent Granule Formulation (HYD-EFG)

Prepared by Hot Melt Extrusion

Ingredient Amount (% Wt.) Hydrochlorthiazide 20 Sodium Bicarbonate 25Citric Acid Anhydrous 25 Avicel PH113 18 Xylitol 10 Crodesta F160 2

Category B

Hydrochlorthiazide Tablet Formulation

Ingredient Amount (% Wt.) HYD-EFG (30-60 mesh) 50 MicrocrystallineCellulose 31 Anhydrous Lactose 10 AcDiSol 2.5 L-HPC LH-11 2.5 Aspartame3 Redberry Flavor 0.4 Magnesium Stearate 0.5 Cab-O-Sil M5P 0.1

The ingredients are dried at elevated temperatures to significantlyreduce the moisture content of each material.

The ingredients in Category A were then blended for 10 minutes andextruded in a hot melt extruder at 70°-100° C. to soften and melt thethermal binders (sucrose stearate and xylitol) and to form granulescontaining the effervescent couple.

Granules are then screened and then blended with the ingredients inCategory B for 5 minutes prior to compression. Hydrochlorthiazidetablets were then compressed to a hardness of approximately 1-3 kg andtablets disintegrate in water in approximately 15-35 seconds.

EXAMPLE 6 Hydromorphone Hydrochloride (8 mg) Fast Melt Tablets for Pain

The present example is provided to demonstrate the utility of thepresent invention for the preparation of formulations useful inalleviating physical pain. Hydromorphone hydrochloride, which is mostuseful as an analgesic in its hydrochloride salt form, is employed inthe present example.

Category A

Effervescent Granule Formulation (HDM-EGF)

Ingredient Amount (% Wt.) Hydromorphine Hydrochloride 15 SodiumBicarbonate 28 Citric Acid Anhydrous 24 Microcrystalline Cellulose 10Anhydrous Lactose 11 Xylitol 10 Sucrose Stearate 2

Category B

Hydromorphine Hydrochloride Tablet Formulation

Ingredient Amount (% Wt.) HDM-EGF (30-60 mesh) 50 MicrocrystallineCellulose 18 Anhydrous Lactose 18 Cross Povidone 5 L-HPC LH-11 5Aspartame 3.25 Natural Orange Powder 0.15 Magnesium Stearate 0.45 FumedSilicon Dioxide 0.15

The ingredients in Category A are dried at elevated temperatures tosignificantly reduce the moisture content of the material.

These ingredients were then blended for 10 minutes and extruded in a hotmelt extruder at 70°-100° C. to soften and melt the thermal binders(sucrose stearate and xylitol) and to form granules containing theeffervescent couple.

Granules were then screened and blended with the ingredients in CategoryB for 5 minutes prior to compression. Hydromorphone tablets were thencompressed to a hardness of approximately 1-5 kg (depending upon thedose of the active) and tablets disintegrate in water in approximately15-35 seconds.

EXAMPLE 7 Fluoxetine Hydrochloride (20 mg) Fast Melt Tablet Formulationto Treat Depression

The present example is provided to demonstrate the utility of thepresent invention for the preparation of fast melt tablet formulationsuseful in treating depression. Fluoxetine hydrochloride, which has itsantidepressant effect via the enhancement of serotonin activity, isemployed in the present example.

Category A

Effervescent Granule Formulation (FLX-EFG)

Prepared by Hot Melt Extrusion

Ingredient Amount (% Wt.) Fluoxetine Hydrochloride 18 Sodium Bicarbonate26 Citric Acid Anhydrous 26 Microcrystalline Cellulose 4 AnhydrousLactose 13 Xylitol 10 Crodesta F160 3

Category B

Fluoxetine Hydrochloride Tablet Formulation

Ingredient Amount (% Wt.) FLX-EFG (20-80 mesh) 50 Anhydrous Lactose 31Microcrystalline Cellulose 10 L-HPC LH-11 5 Aspartame 3 Redberry Flavor0.4 Magnesium Stearate 0.5 Fumed Silicon Dioxide 0.1

The ingredients in Category A are dried at an elevated temperature tosignificantly reduce the moisture content of each material.

The ingredients were then blended for 5-10 minutes and extruded in a hotmelt extruder at approximately 70-100° C. to soften and melt the thermalbinders (sucrose stearate and xylitol) and to form granules containingthe effervescent couple.

The granules were then screened and blended with the ingredients inCategory B for 5 minutes prior to compression. Fluoxethine HCl tabletswere then compressed to a hardness of approximately 1-5 kg (dependingupon the dose of the active) and tablets disintegrate in water inapproximately 15-40 seconds.

EXAMPLE 8 Sumatriptan Succinate (6 mg) Fast Melt Tablet Formulation toTreat Migraind

The present example is provided to demonstrate the utility of thepresent invention for the preparation of succinate formulations usefulin the treatment of migraine headaches. Sumatriptan succinate, aserotonin agonist, is employed in the present example and isadministered via injection in its succinate form.

Category A

Effervescent Granule Formulation (SS-EGF)

Prepared by Hot Melt Extrusion

Ingredient Amount (% Wt.) Sumatriptan Succinate 15 Sodium Bicarbonate 27Citric Acid Anhydrous 26 Microcrystalline Cellulose 11 Anhydrous Lactose9 Xylitol 10 Sucrose Stearate 2

Category B

Sumatriptan Succinate Tablet Formulation

Ingredient Amount (% Wt.) SS-EGF (30-60 mesh) 50 MicrocrystallineCellulose 31 Mannitol 10 L-HPC LH-11 5 Aspartame 3 Redberry Flavor 0.3Natural Orange Powder 0.1 Magnesium Stearate 0.5 Fumed Silicon Dioxide0.1

The ingredients are dried at elevated temperatures to significantlyreduce the moisture content of the materials.

The ingredients were then blended for approximately 10 minutes andextruded in a hot melt extruder at 70°-100° C. to soften and melt thethermal binders (sucrose stearate and xylitol) and to form granulescontaining the effervescent couple.

Granules were then screened and then blended with the ingredients inCategory B for 5 minutes prior to compression. Surnatriptan succinatetablets were then compressed to a hardness of approximately 1-5 kg(depending upon the dose of the active) and tablets disintegrate inwater in approximately 15-35 seconds.

EXAMPLE 9 Levothyroxine Sodium (25 mg) Fast Melt Tablets for DiminishedThyroid Function

The present example is provided to demonstrate the utility of thepresent invention for the preparation of formulations useful in treatinghypothyroidism. Levothyroxine sodium, tablets of which are indicated asreplacement or substitution therapy for diminished or absent thyroidfunction, is employed in the present example.

Category A

Effervescent Granule Formulation (LS-EGF)

Prepared by Hot Melt Extrusion

Ingredient Amount (% Wt.) Levothyroxine Sodium 30 Sodium Bicarbonate 24Citric Acid Anhydrous 24 Anhydrous Lactose 10 Xylitol 10 SucroseStearate 2

Category B

Levothyroxine Sodium Tablet Formulation

Ingredient Amount (% Wt.) LS-EGF (20-80 mesh) 55 MicrocrystallineCellulose 26 Mannitol 10 Cross Povidone 5 Aspartame 3 Redberry Flavor0.4 Magnesium Stearate 0.5 Fumed Silicon Dioxide 0.1

The ingredients in Category A are dried at elevated temperatures tosignificantly reduce the moisture content of each material.

The ingredients were then blended for 10 minutes and extruded in a hotmelt extruder at 70°-100° C. to soften and melt the thermal binders(sucrose stearate and xylitol) and to form granules containing theeffervescent couple.

Granules were then reduced in size and blended with the ingredients inCategory B for approximately 5 minutes prior to compression.Levothyroxine sodium tablets were then compressed to a hardness ofapproximately 1-5 kg (depending upon the dose of the drug) and tabletsdisintegrate in water in approximately 15-35 seconds.

EXAMPLE 10 Simvastatin (10 mg) Fast Melt Tablets to Lower Cholesterol

The present example is provided to demonstrate the utility of thepresent invention for the preparation of fast melt tablet formulationsuseful in treating high cholesterol. Simvastatin, a syntheticallyderived cholesterol lowering agent, is employed in the present example.

Category A

Effervescent Granule Formulation (SV-EGF)

Ingredient Amount (% Wt.) Simvastatin 15 Sodium Bicarbonate 25 CitricAcid Anhydrous 25 Xylitol 12 Microcrystalline Cellulose 15 AnhydrousLactose 6 Crodesta F160 2

Category B

Simvastatin Tablet Formulation

Ingredient Amount (% Wt.) SV-EGF (30-80 mesh) 45 Avicel PH113 31Mannogen 3215 15 L-HPC LH-11 5 Aspartame 3 Redberry Flavor 0.25 NaturalOrange Powder 0.15 Magnesium Stearate 0.5 Fumed Silicon Dioxide 0.1

The ingredients in Category A are dried at elevated temperature in thepresence of a dessicant to significantly reduce the moisture content ofeach material.

These ingredients were then blended for 10 minutes and extruded in a hotmelt extruder at 70-100° C. to soften and melt the thermal binders(sucrose stearate and xylitol) and to form granules containing theeffervescent couple.

Granules were reduced in size and then, blended with the ingredients inCategory B for 5 minutes prior to compression. Simvastatin tablets werethen compressed to a hardness of approximately 1-5 kg (depending uponthe dose of the drug) and tablets disintegrate in water in approximately15-35 seconds.

EXAMPLE 11 Ergotamine Tartrate (2 mg) Fast Melt Tablets to TreatMigraine

The present example is provided to demonstrate the utility of thepresent invention for the preparation of a fast melt tablet formulationeffective in the treatment of migraine headaches. Ergotamine tartrate,an alpha adrenergic blocking agent which produces depression of centralvasomotor centers, is the therapeutic drug employed in the presentexample.

Category A

Effervescent Granule Formulation (EGT-EGF)

Prepared by Hot Melt Extrusion

Ingredient Amount (% Wt.) Ergotamine Tartrate 10 Sodium Bicarbonate 27Citric Acid Anhydrous 22 Avicel PH113 15 Xylitol 15 L-HPC LH-11 5Fujicalin SG 4 Crodesta F160 2

Category B

Ergotamine Tartrate Tablet Formulation

Ingredient Amount (% Wt.) EGT-EGF (20-80 mesh) 55 MicrocrystallineCellulose 26 Mannitol 10 AcDiSol 2.5 L-HPC LH-11 2.5 Aspartame 3Redberry Flavor 0.4 Magnesium Stearate 0.5 Fumed Silicon Dioxide 0.1

The ingredients in Category A were dried to significantly reduce themoisture content of each material.

These ingredients were then blended for 10 minutes and extruded in a hotmelt extruder to soften and melt the thermal binders (sucrose stearateand xylitol) and to form granules containing the effervescent couple.

Granules were then passed through a #20 screen and then blended with theingredients in Category B for 5 minutes prior to compression. Ergotaminetartrate tablets were then compressed to a hardness of approximately 1-5kg and tablets disintegrate in water in approximately 15-35 seconds.

EXAMPLE 12 Preparation of Effervescent Granules

The following general procedure can be used to prepare a variety ofeffervescent granules according to the present invention.

All materials to be used are passed through a fine screen (100 mesh).The materials are then dried at 40° C. for 24 hours, preferably in avacuum. The following steps are conducted in an atmosphere having a lowrelative humidity. All materials are then mixed in a twin shell blenderfor 5-10 minutes until a uniform blend is achieved. Then, using ahot-melt extrusion apparatus, the powder blend is subjected to atemperature of less than or equal to about 120° C. at a rate and for aperiod of time sufficient to melt or soften the binder to formagglomerates of the effervescent couple in an extrudant which is eitherchopped or ground. The extruded granules are then screened and stored ata low relative humidity for subsequent incorporation into a variety ofpharmaceutical dosage forms.

The following materials can be used to prepare the effervescent granulesaccording to the procedure just described.

A. Ingredients Amount (% Wt.) NaHCO₃ 52 Citric Acid 14 Tartaric Acid 28PEG 1,000 6

B. Ingredients Amount (% Wt.) NaHCO₃ 55 Citric Acid 13.5 Tartaric Acid24 PEG 4,000 7.5

C. Ingredients Amount (% Wt.) Sodium Glycine Carbonate 58 Citric Acid 15Tartaric Acid 21 Pluronic F68 6

D. Ingredients Amount (% Wt.) NaHCO₃ 54 Citric Acid 16 Tartaric Acid 24PEG 20,000 3 PEG 400 3

E. Ingredients Amount (% Wt.) NaHCO₃ 50 Citric Acid 14 Tartaric Acid 28PEG 8,000 8

F. Ingredients Amount (% Wt.) KHCO₃ 62 Fumaric Acid 5 Citric Acid 8Tartaric Acid 18 PEG 6,000 7

G. Ingredients Amount (% Wt.) NaHCO₃ 55 NaH₂PO4 37.5 Pluronic F127 7.5

H. Ingredients Amount (% Wt.) NaHCO₃ 54 Fumaric Acid 3 Maleic Acid 5Citric Acid 13 Tartaric Acid 18 PEG 3,350 6 Pluronic F68 4

I. Ingredients Amount (% Wt.) NaHCO₃ 56 Citric Acid 37 Cetyl alcohol 4Stearyl alcohol 5

J. Ingredients Amount (% Wt.) NaHCO₃ 51 Citric Acid 34 Xylitol 15

K Ingredients Amount (% Wt.) NaHCO₃ 50 Citric Acid 40 Xylitol 10

In example K, xylitol and citric acid are first hot melt extruded toform a eutectic mixture which is then hot melt extruded with NaHCO₃ toform the effervescent granule.

Table 1 is presented to demonstrate the utility of the present inventionas used together with granules that effervesce relatively rapidly in thepresence of water. These granules may then be formulated into a tabletor other dose compatible and convenient form. These granules are to beprepared by hot melt extrusion as described herein, as well as modifiedprocesses thereof.

TABLE 1 Rapidly effervescent granules in contact with water. HME-ECGranulations Formulation Formulation Formulation Formulation L M N OExcipient % w/w % w/w % w/w % w/w PEG 3350 10 10 10 10 Sodium 10 10 1010 Bicarbonate Sodium 30 0 0 0 Carbonate, fine powder Potassium 0 25 2830 Carbonate, fine powder Citric Acid, 40 35 37 40 anhydrous Xylitol, 00 8 10 granular Xylitol, fine 0 10 0 0 powder Kollodion ® 10 10 0 0 CLAcDiSol ® 0 0 7 0

Table 2 is presented to demonstrate the utility of the above describedrapidly effervescence granules that contain xylitol. These granules areprepared by a hot-melt extrusion process.

TABLE 2 HME-EC Granules With Xylitol Formulation Formulation FormulationFormulation P Q R S Excipient % w/w % w/w % w/w % w/w PEG 3350 6.5 6.56.5 6.5 Sodium 10 10 10 10 Bicarbonate Sodium 30 0 0 0 Carbonate, finepowder Potassium 0 25 28 30 Carbonate, fine powder Citric Acid, 40 35 3740 anhydrous Xylitol, 3.5 8 10 granular Xylitol, fine 3.5 10 3.5 3.5powder Kollodion ® 10 10 0 0 CL AcDiSol ® 0 0 7 0

EXAMPLE 13 Determination of Effervescent Granule Dissolution Rate

This is a visual end-point test for determining effervescent granulesolubility.

Effervescent granules (2.0 grams) were added rapidly in one portion to avery gently stirred (less than 60 rpm) beaker containing water (1.0 L)at about 20°-25° C. The endpoint was visually determined by observingcessation of effervescence or complete dissolution of effervescentgranules.

EXAMPLE 14 Preparation of Tablets Containing Effervescent Granules

The following general procedure can be used to prepare a wide variety oftablet dosage forms containing the effervescent granules of theinvention. It should be understood that the ingredients listed below aremerely representative and can be replaced by many other equivalentcompounds. Any of the effervescent granules detailed here as granules Athrough S may be employed where effervescent granule (EG) is indicatedin the following tablet formulations.

A. Ingredients Amount (% Wt.) Effervescent Granule (EG) 40 DicalciumPhosphate 10 Microcrystalline Cellulose (MCC) 5 Calcium Stearate 2.5Silicon Dioxide 1.0 APAP 41.5

B. Ingredients Amount (% Wt.) EG 50 Pseudoephedrine HCI 20 Mannitol 29Magnesium Stearate 0.5 Silicon Dioxide 0.5

C. Ingredients Amount (% Wt.) EG 25 MCC 15 Diltiazem 10 Lactose 47Magnesium Stearate 0.5 Silicon Dioxide 0.5 Aspartame 1 Grape Flavor 1

D. Ingredients Amount (% Wt.) APAP 60 EG (C) 8 Mannitol 30 Aspartame 1.5Magnesium Stearate 0.5

(C) refers to EG made according to Example I using ingredients listedunder C.

E. Ingredients Amount (% Wt.) Aspirin 50 Mannitol 15 AVICEL PH 101 25.5Aspartame 1.5 Stearic Acid 2 EG (B) 6

F. Ingredients Amount (% Wt.) APAP 55 ACT-DI-SOL 3 EG (A) 8 AVICEL PH10110 Mannitol 22 Aspartame 1.5 Magnesium Stearate 0.5

G. Ingredients Amount (% Wt.) CPM 1 EG (A) 8 AVICEL PH101 26.5 Mannitol62 Magnesium Stearate 0.5 Aspartame 2

Table 3 is presented to demonstrate effervescing granules in aconvenient dose form. In this table, the dose form is a tablet. However,any number of other dose forms may be employed in providing a patientready therapeutic of the present granulations.

TABLE 3 Hot-Melt Extruded-Effervescent Couple (Tablet Formulations)Effervescent tablets contains effervescent granules prepared by hot-meltextrusion. Tablet Formulation H Tablet Formulation I % w/w Excipient %w/w 32.0 APAP 32.0 20.0 (formulation y) EG 25.0 (granulation s) 28.0Mannitol, fine powder 26.0 8.0 Emcocel ® LM50 5.0 5.0 Kollodion ® CL 5.05.0 Aspartame 5.0 0.7 Flavor, grape 0.7 0.4 Lake, lavender 0.4 0.3Cab-O-Sil ® M5P 0.3 0.6 Magnesium Stearate 0.6

Generally, the listed ingredients are thoroughly mixed in a low relativehumidity environment to form a tableting mixture. All the ingredientswill generally pass through a 20 mesh screen. The tableting mixture istableted in a conventional tableting press.

EXAMPLE 15 Preparation of Effervescent Reconstitutable dry Beverage Base

The following ingredients are thoroughly mixed in the amounts specified:Fries & Fries grapefruit flavoring #91470 (5.0 g), fructose USP (30.0g), aspartame (0.5 g), and effervescent granule (2.0 g, preparedaccording to Example 1B). An active ingredient can optionally be addedto this formulation. The above mixture will generally be reconstitutedby adding water until solids reach 10% by weight of the finalformulation.

EXAMPLE 16 Drug-containing hot Melt Extrudable Effervescent Granulations

The following examples are presented to demonstrate the utility of thepresent invention in the preparation of drug-containing granules. Thedrugs identified in Table 4 are for representative purposes only, asmany other pharmacologically agents may be similarly included alone orin combination in the granulation process employing techniques known tothose of ordinary skill in the art.

TABLE 4 Drug-Containing Hot-Melt Extruded Effervescent FormulationsIbuprofen 50 50 0 0 0 30 Chlorphesinamine 0 0 5 5 0 5 MaleatePseudoephridine 0 0 0 25 20 HCl AcDiSol 5 5 0 0 5 5 Microcrystalline 2010 32 20 5 Cellulose Na Bicarbonate 13 13 15 18 20 15 Citric Acid 12 1214 15 18 13 PEG 3350 0 10 14 12 10 12 Crosslinked PVP 0 0 5 3 3 3Explotab 0 0 0 2 2 Mannitol 0 0 5 9 Xylitol 0 0 10 15 10

EXAMPLE 17 Preparation of Effervescent Suspension

The following ingredients are thoroughly mixed in the amounts specified:effervescent granule (59 g), bentonite (35 g) and BENLATE (6 g, fromE.I. DuPont). The resulting mixture is suspended by adding approximately1000 ml of water prior to spraying.

It is contemplated that this preparation may be used for example as aspray suitable for application to plants. The instantaneous dispersionof active ingredients provided through use of the present formulationsreduces caking and agglomeration of the active ingredient onto surfaces.

EXAMPLE 18 Tablets

The present example is presented to demonstrate the formulation oftablets from the granules described herein.

The granules provided herein may be compressed into tablets with theoptional addition of lubricants, glidants, disintegrants, and othertablet excipients that are well known in the art.

After suitable processing of the granules to the desired particle size,the lubricants (e.g., 1%-1.5% @ stearic acid, magnesium stearate @0.05,Prv=Sodium stearyl furnarate @2%), glidants (talc, silicon dioxide,cabosil M5P) and/or other excipients (flavorants, disintegrants,colorants and anti-oxidants) that are known in the art, are blendedprior to compression into tablets or other solid dosage forms known tothose of skill in the art. These granulations may also be packaged forindividual dosage use upon mixture with an appropriate liquid, such aswater or other liquid vehicle suitable for ingestion.

The granules and tablets containing the granules of the invention mayalso include, by way of example, H2 antagonists (e.g., anitidine),cardiovascular drugs, (e.g., dilitizan hydrochloride), local anesthetic(e.g., lidocaine hydrochloride), anti fungal agent (e.g., miconazole),antibiotics (e.g., erythromycin), anti-cancer agents (coated for gastricrelease) (e.g., methotrexate), and tranquilizers (e.g. amitryptoline).

EXAMPLE 19 Preparation of a Vaginal Tablet Comprising SlowlyEffervescing Effervescent Granuses

One thousand layered tablets are prepared as follows:

(a) Miconazole: 300 gm

(b) Hydroxypropylmethylcellulose (400 cps): 100.0 gm

(c) Mannitol: 100.0 gm

(d) Corn starch: 6.0 gm

(e) Zinc stearate: 3.6 gm

(f) Effervescent granule (1E): 50 gm

Using a suitable mixer, the miconazole, mannitol andHydroxypropylmethylcellulose are mixed well via geometric dilution. Themixture is mixed in a Fitzmill quipped with a No. 000 screen andgranulated using a 5% starch paste prepared by adding the corn starch toapproximately 115 ml of water. Additional water is added as required tomake a suitable granulation. The resulting granulation is wet-screenedusing a No. 2 screen and tray dried at 40° C. to 50° C. for 8 to 12hours. The dried granulation is ground and passed through a No. 10screen. Zinc stearate and effervescent granule, which has passed througha No. 20 screen, is added to the granulation, mixed well and theresulting slow release effervescent granulation reserved for tabletcompression.

Using a suitable layer press, such as the Manesty Layer Press, the slowrelease granulation is added to the adjusted die cavity to provide alayer having a weight of approximately 500 mg. The final compressionpressure is adjusted to provide a suitable tablet with a total weight ofapproximately 0.5 g.

The principles, preferred embodiments and modes of operation of thepresent invention have been described in the foregoing specification.The invention which is intended to be protected herein, however, is notto be construed as limited to the particular embodiments disclosed,since these are to be regarded as illustrative rather than restrictive.Variations and changes may be made by others without departing from thespirit and scope of the invention.

EXAMPLE 20 Ondansetron HCL (8 mg) Anti-emetic

The present example is provided to demonstrate the utility of thepresent invention for the preparation of formulations useful in treatingnausea and vomiting induced by cytotoxic chemotherapy and radiation.

A. Effervescent Granule Formulation (OND-EGF)

Prepared by Hot Melt Extrusion

Ingredient Amount (% Wt.) Ondansetron HCI 8 Sodium Bicarbonate 25 CitricAcid Anhydrous 25 Avicel PH113 12 Sorbitol 14 Xylitol 11 Poloxomer 5

B. Ondansetron HCl Tablet Formulation

Ingredient Amount (% Wt.) OND-EGF (2-0-80 mesh) 50 MicrocrystallineCellulose 31 Mannitol 10 AcDiSol 5 Acesulfame Potassium 3 RedberryFlavor 0.4 Magnesium Stearate 0.5 Fumed Silicon Dioxide 0.1

Ingredients in Category A are dried at 40°-60° C. to significantlyreduce the moisture content of each material.

The ingredients in Category A were then blended for 10 minutes andextruded in a hot melt extruder at 70°-100° C. to soften and melt thethermal binders (poloxomer and xylitol) and to form granules containingthe effervescent couple.

Granules were then screed and blended with the ingredients in Category Bfor 5 minutes prior to compression. Ondansetron tablets were thencompressed to a hardness of approximately 1-3 kg and tabletsdisintegrate in water at 37° C. in approximately 15-35 seconds.

EXAMPLE 21 Loratadine (10 mg) Fast Melt Tablets-antihistamine

The present example is provided to demonstrate the utility of thepresent invention for the preparation of antihistamine formulationsuseful in treating allergies and cold and flu symptoms. Loratadine isthe therapeutic drug employed in the present example.

A. Effervescent Granule Formulation (LOR-EFG) Prepared by Hot MeltExtrusion

Ingredient Amount (% Wt.) Loratadine 10 Sodium Bicarbonate 25 CitricAcid Anhydrous 25 Microcrystalline Cellulose 14 xylitol 10 Poloxmer 6

B. Loratadine Tablet Formulation

Ingredient Amount (% Wt.) LOR-EFG (30-60 mesh) 50 MicrocrystallineCellulose 31 Anhydrous Lactose 10 AcDiSol 2.5 L-HPC LH-11 2.5 AcesulfamePotassium 3 Citrus Flavor 0.4 Magnesium Stearate 0.5 Cab-O-Sil MSP 0.1

The ingredients are dried at 40° C. under a vacuum to significantlyreduce the moisture content of each material.

The ingredients in Category A were then blended for 10 minutes andextruded in a hot melt extruder at 70°-100° C. to soften and melt thethermal binders (poloxomer and xylitol) and to form granules containingthe effervescent couple.

Granules are then screened and then blended with the ingredients inCategory B for 5 minutes prior to compression. Loratadine tablets werethen compressed to a hardness of approximately 1-3 kg and tabletsdisintegrate in water at 37° C. in approximately 15-35 seconds.

EXAMPLE 22 Selegiline Hydrochloride (8 mg) Fast Melt Tablets forParkinson's Disease

The present example is provided to example to demonstrate the utility ofthe present invention for the preparation of formulations useful in thetreatment of Parkinson's Disease. Selegiline hydrochloride, which ismost useful in its hydrochloride salt form, is employed in the presentexample.

A. Effervescent Granule Formulation (SEL-EGF)

Ingredient Amount (% Wt.) Selegiline Hydrochloride 15 Sodium Bicarbonate28 Citric Acid Anhydrous 24 Microcrystalline Cellulose 10 Sorbitol 8Xylitol 10 Poloxmer 5

B. Selegiline Hydrochloride Table Formulation

Ingredient Amount (% Wt.) SEL-EGF (30-60 mesh) MicrocrystallineCellulose Anhydrous Lactose Cross Povidone L-HPC LH-11 AcesulfamePotassium Natural Orange Powder Magnesium Stearate Fumed Silicon Dioxide

The ingredients in Category A are dried at 40° C. under a high vacuum tosignificantly reduce the moisture content of the material.

The ingredients were then blended for 10 minutes and extruded in a hotmelt extruder at 70°-100° C. to soften and melt the thermal binders(poloxomer and xylitol) and to form granules containing the effervescentcouple.

Granules are then screened and blended with the ingredients in CategoryB for 5 minutes prior to compression. Selegiline tablets were thencompressed to a hardness of approximately 1-3 kg and tabletsdisintegrate in water at 37° C. in approximately 15-35 seconds.

EXAMPLE 23 Ketorolac Tromethamine (10 mg) Fast Melt Tablet Formulationto Treat Moderately Severe Acute Pain

The present example is provided to demonstrate the utility of thepresent invention for the preparation of fast melt tablet formulationsuseful in treating pain. Ketorolac tromethamine is a NSAID and isemployed in the present example.

A. Effervescent Granule Formulation (FLX-EPG) Prepared by Hot MeltExtrusion

Ingredient Amount (% Wt.) Ketorolac tromethamine 10 Sodium Bicarbonate26 Citric Acid Anhydrous 26 Microcrystalline Cellulose 9 Sorbitol 13Xylitol 10 Poloxomer 6

B. Ketorolac tromethamine Table Formulation

Ingredient Amount (% Wt.) KET-EFG (20-80 mesh) 40 Mannitol 26Microcrystalline Cellulose 25 L-HPC LH-11 5 Aceulfame Potassium 3 CitrusFlavor 0.4 Magnesium Stearate 0.5 Fumed Silicon Dioxide 0.1

The ingredients in Category A are dried at 40° C. under a high vacuum tosignificantly reduce the moisture content of the material.

The ingredients were then blended for 5-10 minutes and extruded in a hotmelt extruder at approximately 70°-100° C. to soften and melt thethermal binders (poloxomer and xylitol) and to form granules containingthe effervescent couple.

Granules are then screened and blended with the ingredients in CategoryB (previously dried to reduce moisture content), for 5 minutes prior tocompression. Ketorolac tromethamine tablets were then compressed to ahardness of approximately 1-3 kg and tablets disintegrate in water at37° C. in approximately 15-40 seconds.

EXAMPLE 24 Prochlorperazine (10 mg) Fast Melt Tablet Formulation toTreat Nausea and Vomiting

The present example is provided to demonstrate the utility of thepresent invention for the preparation of prochlorperazine formulationsuseful in the treatment of nausea and vomiting.

A. Effervescent Granule Formulation (PCP-EGF) Prepared by Hot MeltExtrusion

Ingredient Amount (% Wt.) Prochlorperazine 10 Sodium Bicarbonate 27Citric Acid Anhydrous 26 Microcrystalline Cellulose 12 Sorbitol 9Xylitol 10 Polyethylene Oxide 6

B. Prochlorperzine Tablet Formulation

Ingredient Amount (% Wt.) PCP-EGF (30-60 mesh) 50 MicrocrystallineCellulose 31 Mannitol 10 L-HPC LH-11 5.0 Aceulfame Potassium 3.0 CitrusFlavor 0.3 Natural Orange Powder 0.1 Magnesium Stearate 0.5 FumedSilicon Dioxide 0.1

The ingredients are dried at 40° C. under a high vacuum to significantlyreduce the moisture content of the materials.

The ingredients were then blended for approximately 10 minutes andextruded in a hot melt extruder at 70°-100° C. to soften and melt thethermal binders (polyethylene oxide and xylitol) and to form granulescontaining the effervescent couple.

Granules were then screened and then blended with the ingredients inCategory B (previously dried) for 5 minutes prior to compression.Prochlorperazine tablets were then compressed to a hardness ofapproximately 1-3 kg (depending upon the dose of the active) and tabletsdisintegrate in water at 37° C. in approximately 15-35 seconds.

REFERENCES

The following references, to the extent they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

1. U.S. Pat. No. 1,262,888 (April 1918) to Westlake

2. U.S. Pat. No. 3,962,417 (June 1976) to Howell

3. U.S. Pat. No. 4,613,497 (September 1986) to Chaukin

4. U.S. Pat. No. 4,639,368 (January 1987) to Niazi

5. U.S. Pat. No. 4,687,662 (August 1987) to Schobel

6. U.S. Pat. No. 4,725,427 (February 1988) to Ashmead

7. U.S. Pat. No. 4,753,792 (June 1988) to Aberg

8. U.S. Pat. No. 4,940,588 (July 1990 to Sparks

9. U.S. Pat. No. 5,055,306 (February 1991) to Barry

10. U.S. Pat. No. 3,667,929 (June 1972) to Fleming

11. U.S. Pat. No. 4,153,678 (May 1979) to Quinlan

12. U.S. Pat. No. 4,267,164 (May 1981) to Yeh et al.

13. U.S. Pat. No. 5,100,674 (March 1992) to Ser et al.

14. U.S. Pat. No. 5,178,878

15. Pharmaceutical Dosage Forms-Tablets vol. 1, 2nd edition, Herbert A.Lieberman, ed. pp. 372-376.

16. BE664197 (November 1965)

17. EP0189114 (July 1986)

18. EP0190689 (August 1986)

19. EP0217631 (April 1987)

20. DE1938709 (April 1970)

21. DE2020893 (November 1970)

22. DE2213604 (June 1973)

23. GB917456 (February 1963)

24. GB1055854 (January 1967)

25. GB1276839 (June 1972)

26. GB1300998 (December 1972)

27. GB 1370766 (October 1974)

28. GB2019844 (November 1979)

29. GB2083997 (April 1982)

30. EP0396335 (November 1990)

31. GB0003160 (October 1872)

What is claimed is:
 1. An effervescent granule having a controllablerate of effervescence comprising: a mixture consisting essentially of anacidic agent, pharmacologically active agent, a hot-melt extrudablebinder and optionally a plasticizer; and an alkaline agent; theeffervescent granule made by an essentially water free and essentiallysolvent free thermal heat process comprising: dry blending said mixture;and hot-melt extruding said blended mixture to form an effervescentgranule.
 2. The effervescent granule of claim 1, wherein thepharmacologically active agent is a phenanthrene derivative.
 3. Theeffervescent granule of claim 1, wherein the phenanthrene derivative ismorphine sulfate.
 4. The effervescent granule of claim 2, wherein thepharmacologically active agent is a synthetic anti-diarrheal agent. 5.The effervescent granule of claim 1, wherein the pharmacologicallyactive agent anti-diarrheal agent is loperamide hydrochloride.
 6. Theeffervescent granule of claim 1, wherein the pharmacologically activeagent is an antiviral agent.
 7. The effervescent granule of claim 6,wherein the antiviral agent is acyclovir.
 8. The effervescent granule ofclaim 1, wherein the pharmacologically active agent is an anxiolyticagent.
 9. The effervescent granule of claim 8, wherein the anxiolyticagent is buspirone.
 10. The effervescent granule of claim 1, wherein thepharmacologically active agent is a diuretic agent.
 11. The effervescentgranule of claim 10, wherein the diuretic agent is hydrochlorthiazide.12. The effervescent granule of claim 1, wherein the narcotic is amorphine derivative.
 13. The effervescent granule of claim 12, whereinthe morphine derivative is hydromorphone hydrochloride.
 14. Theeffervescent granule of claim 1, wherein the pharmacologically activeagent is an antidepressant.
 15. The effervescent granule of claim 14,wherein the antidepressant is fluoxetine hydrochloride.
 16. Theeffervescent granule of claim 1, wherein the pharmacologically activeagent is a serotonin agonist.
 17. The effervescent granule of claim 16,wherein the serotonin agonist is sumatriptan succinate.
 18. Theeffervescent granule of claim 1, wherein the pharmacologically activeagent is a levorotatory isomer of thyroxin.
 19. The effervescent granuleof claim 18, wherein the levorotatory isomer is levothyroxine sodium.20. The effervescent granule of claim 1, wherein the pharmacologicallyactive agent is a cholesterol lowering agent.
 21. The effervescentgranule of claim 20, wherein the cholesterol lowering agent issimvastatin.
 22. The effervescent granule of claim 1, wherein thepharmacologically active agent is an alpha adrenergic blocking agent.23. The effervescent granule of claim 21, wherein the alpha adrenergicblocking agent is ergotamine tartrate.
 24. The effervescent granule ofclaim 1 wherein the effervescent granule is formulated into a tablet.25. The effervescent granule of claim 1 that also contains andantioxidant.
 26. The effervescent granules of claim 1 wherein thepharmacologically active agent is ondansetron.
 27. The effervescentgranules of claim 1 wherein the pharmacologically active agent isloratadine.
 28. The effervescent granule of claim 1 wherein thepharmacologically active agent is selegiline hydrochloride or ahydrochloride salt form.
 29. The effervescent granules of claim 1wherein the pharmacologically active agent is ketorolac tromethamine.30. The effervescent granules of claim 1 wherein the pharmacologicallyactive agent is prochlorperazine.